Microvascular issues can precede major macrovascular diseases and their measurements can predict long-term cardiovascular disease and survival. Therefore, early interventions on microvascular... Show moreMicrovascular issues can precede major macrovascular diseases and their measurements can predict long-term cardiovascular disease and survival. Therefore, early interventions on microvascular issues can potentially delay later cardiovascular problems. Microcirculation is critical for tissue perfusion, exchange of nutrients, oxygen and carbon dioxide between blood and interstitial fluid, and in vascular homeostasis. Assessing the microcirculation is challenging due to spatially heterogeneous structure and variability in perfusion over time and under different conditions.The thesis aims to evaluate standardized techniques for investigating microcirculation. Although numerous techniques are used to assess microvasculature, there's no consensus on which is the most suitable for evaluating microcirculation. The dissertation also explores the possibilities and impossibilities of measuring the microvasculature for pharmacodynamic outcomes of new interventions and medications, and highlights the need for further research to develop effective interventions targeting microcirculation. Show less
Manen, L. van; Birkhoff, W.A.J.; Eggermont, J.; Hoveling, R.J.M.; Nicklin, P.; Burggraaf, J.; ... ; Dijkstra, J. 2021
Background: Tissue necrosis, a consequence of inadequate tissue oxygenation, is a common post-operative complication. As current surgical assessments are often limited to visual and tactile... Show moreBackground: Tissue necrosis, a consequence of inadequate tissue oxygenation, is a common post-operative complication. As current surgical assessments are often limited to visual and tactile feedback, additional techniques that can aid in the interrogation of tissue viability are needed to improve patient outcomes. In this bi-institutional pilot study, the performance of a novel snapshot hyperspectral imaging camera to detect superficial cutaneous oxygen saturation (StO(2)) was evaluated.Methods: Healthy human volunteers were recruited at two participating centers. Cutaneous StO(2) of the forearm was determined by a snapshot hyperspectral camera on two separate study days during occlusionreperfusion of the brachial artery and after induction of local vasodilation. To calculate the blood StO(2) at each pixel in the multispectral image, spectra were selected, and fitting was performed over wavelengths ranging from 470 to 950 nm.Results: Quantitative detection of physiological changes in cutaneous StO(2) levels was feasible in all sixteen volunteers. A significant (P<0.001) decrease in cutaneous StO(2) levels from 78.3% (SD: 15.3) at baseline to 60.6% (SD: 19.8) at the end of occlusion phase was observed, although StO(2) levels returned to baseline after five minutes. Mean cutaneous StO(2) values were similar in the same subjects on separate study days (Pearson R2: 0.92 and 0.77, respectively) at both centers. Local vasodilation did not yield significant changes in cutaneous StO(2) values.Conclusions: This pilot study demonstrated the feasibility of a snapshot hyperspectral camera for detecting quantitative physiological changes in cutaneous StO(2) in normal human volunteers, and serves as a precursor for further validation in perioperative studies. Show less
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic... Show moreReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain-penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK1 inhibition in peripheral blood mononuclear cells in a first-in-human, placebo-controlled, double-blind, randomized single-ascending dose (SAD) and multiple-ascending dose (MAD) study. DNL104 was well-tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was observed in the MAD, and assessed to be drug related. We demonstrate that DNL104 leads to RIP1 kinase inhibition, and this is not associated with central nervous system (CNS) toxicities, supporting future development of CNS penetrant RIPK1 inhibitors. Show less
Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath... Show moreConcentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol. Show less
